The goal of this Program Project Grant (PPG) revised renewal application is to establish mechanisms underlying asthma inception and exacerbation during childhood and adolescence. The three projects and cores of this PPG application have collaborated extensively and effectively over the past decade using the ROI (COAST I) and PPG (COAST ll-lll) funding mechanisms and this integrated and multidisciplinary approach (immunology, microbiology, physiology, and genetic) has resulted in multiple novel and seminal observations into the inception of asthma. Our central theme is that human rhinovirus (HRV) infections during childhood and adolescence contribute mechanistically to the development of specific phenotypes of childhood wheezing and asthma (inception) due to abnormal host immune response pathways that are independent, genetically regulated, and have HRV as a common intersection point. Furthermore, once asthma is established, our preliminary data suggest that HRVs interact with specific airway bacteria to modulate respiratory symptom severity and promote asthma exacerbations, and that immune response profiles can additionally modify these asthma phenotypes based on age and gender. The current PPG renewal application is highly innovative from the standpoints of original hypotheses, study design, and analytical approaches. First, our preliminary data has led to the hypothesis that risk for asthma inception is related to genetic variation in at least two independent pathways that have HRV wheezing illnesses as a common link in early life. Second, from a study design standpoint, the extensive longitudinal immunologic, microbiologic, genetic and physiologic phenotyping that has and will continue to be performed provides a unique data set and future opportunity to integrate asthma phenotype development to age, gender, and to the natural history of asthma itself. Third, we propose to use a unique study design that will evaluate viral and bacterial (and the microbiome) interactions, vitamin D receptor genotype and vitamin D levels in both children with asthma and cohort control subjects as they relate to respiratory symptom burden and the development of asthma exacerbations. Fourth, from a technical perspective, we propose to use state-of-the-art genetic analyses that will involve miRNA evaluations, epigenetics, and gene expression studies all in the same airway samples (nasal epithelial cells). The proposed studies will provide greater mechanistic understanding and new approaches that are needed to address the important therapeutic gap in treatment and prevention of HRV and bacterial illnesses as they relate to both asthma inception and exacerbations.